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Lipopeptides as tools in catalysis, supramolecular, materials and medicinal chemistry

Nature Reviews Chemistry volume 7, pages 710–731 (2023)Cite this article

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Abstract

Lipopeptides are amphiphilic peptides in which an aliphatic chain is attached to either the C or N terminus of peptides. Their self-assembly — into micelles, vesicles, nanotubes, fibres or nanobelts — leads to applications in nanotechnology, catalysis or medicinal chemistry. Self-organization of lipopeptides is dependent on both the length of the lipid tail and the amino acid sequence, in which the chirality of the peptide sequence can be transmitted into the supramolecular species. This Review describes the use of lipopeptides to design synthetic advanced dynamic supramolecular systems, nanostructured materials or self-responsive delivery systems in the area of medical biotechnology. We examine the influence of external stimuli, the ability of lipopeptide-derived structures to adapt over time and their application as medicinal agents with antibacterial, antifungal, antiviral or anticancer activities. Finally, we discuss the catalytic efficiency of lipopeptides, with the aim of building minimal synthetic enzymes, and recent efforts to incorporate metals into lipopeptide assemblies.

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Fig. 1: Synthesis, self-assembly and characterization of lipopeptides.
Fig. 2: Structural motifs and external stimuli determine self-assembly and properties of lipopeptides.
Fig. 3: Applications of lipopeptides in nanostructured and advanced materials.
Fig. 4: Applications of lipopeptides as dynamic and responsive species.
Fig. 5: Bioinspired therapeutic lipopeptides.
Fig. 6: Bioactive lipopeptides.
Fig. 7: Applications of lipopeptides as cell-membrane transporters and drug and gene delivery.
Fig. 8: Metal-free catalysed reactions using lipoamino acids and lipopeptides.
Fig. 9: Transition-metal-catalysed reactions using lipoamino acids and lipopeptides.

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Acknowledgements

The authors acknowledge funding from La Caixa Foundation under the Junior Leader Program (Nos. LCF/BQ/PI19/11690020, ID 100010434), CAM-Atracción de Talento (2019-T1/IND-12683), PID2019-106327GA-I00 (MCIN/AEI/10.13039/501100011033), RyC2019-026674-I (MCIN/AEI/10.13039/501100011033 and FSE) and PIE 20218AT015 (CSIC).

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  1. IMDEA-Nanociencia, Madrid, Spain

    Cesar Vicente-Garcia & Ignacio Colomer

  2. Instituto de Química Orgánica General (IQOG-CSIC), Madrid, Spain

    Ignacio Colomer

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  1. Cesar Vicente-Garcia
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Correspondence to Ignacio Colomer.

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Glossary

Aerogel

Solid ordered structure obtained by displacing the liquid component of a gel using a gas, initially developed under supercritical conditions, with slight or no shrinkage and retaining its original shape.

Critical aggregation concentration

(CAC). Minimal concentration of an amphiphile at which self-assembled ordered structures are formed and detected.

Haemolysis

Disruption of erythrocyte membranes, causing the release of haemoglobin, either by an external agent or natural necrosis at the end of erythrocyte life.

Half-maximal inhibitory concentration (IC50)

The concentration of a substance required for 50% inhibition of a specific biological function, used as a measure of drug potency.

Hydrogel

Hydrophilic self-assembled (macro)molecule that is not soluble in water, but absorbs large amounts of water, maintaining well-defined supramolecular structure.

Hydrophilic–lipophilic balance

Measure of the hydrophilic and lipophilic degree of a surfactant molecule that results from its partition between oil and water.

Hydrophobic collapse

Entropy-driven process, commonly observed by polypeptides and amphiphilic species in polar solvents, that produces a more stable 3D conformation as a result of the inability to interact or stabilize the hydrophobic domain by polar solvents.

Langmuir–Blodgett film

Nanostructure formed by organized (multi)layers of amphiphilic molecules, or nanoparticles, as a result of transferring an organized monolayer film from a liquid–air interface into a solid support.

Low-molecular-weight gelators

Small molecules that self-assemble via noncovalent bonding, entrapping molecules of solvent, commonly forming fibres, giving rise to gels.

Matrix metalloprotein-7

(MMP-7). Also known as matrilysin or pump-1 protease (PUMP-1) is a zinc-dependent endonuclease that breaks down macromolecules from the extracellular matrix.

Melanocortin 1 receptor

G-coupled receptor binding to pituitary peptide hormones, normally expressed by melanocytes and overexpressed by melanoma cancerous cells.

Membrane depolarization

A shift in electric charge distribution (potential) within the cell membrane, related to ion transport, that can be physiological, that is, action potential, or lethal, that is antibiotics mechanism.

Minimal inhibitory concentration

(MIC). Lowest concentration of an antimicrobial agent that inhibits the growth of a microorganism.

Multiresistant bacteria

Bacterial strains showing resistance to at least one antimicrobial drug in three or more antimicrobial categories.

Nonribosomal peptide synthetases

Multimodular enzymes that synthesize natural peptides, frequently incorporating non-proteinogenic amino acids and structural modifications, which is an alternative mechanism independent of mRNA, as opposed to ribosomes.

Organogel

Gel formed by an organic liquid and a 3D cross-linked structure, formed by polymerization of reactive monomers or by self-assembling of low-molecular-weight species via noncovalent bonding, retaining the organic solvent.

Stern layer

The first (internal) layer of the electric double layer, which forms at a charged surface in an ionic solution.

Xerogels

Solid ordered structure obtained by drying a gel, for example, evaporating water from a hydrogel, with a notable shrinkage and usually not retaining its original shape.

Zeta potential

Electric potential in the interfacial double layer of a colloidal dispersion, nanoparticle or self-assembled structure with respect to bulk medium, providing a measure of its stability.

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Vicente-Garcia, C., Colomer, I. Lipopeptides as tools in catalysis, supramolecular, materials and medicinal chemistry. Nat Rev Chem 7, 710–731 (2023). https://doi.org/10.1038/s41570-023-00532-8

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